B r e a s t Cancer Vol. 9 No. 2 April 2002

Review Art ic le

Quality of Life Assessment

Koiiro Shimozuma *~'2

Health-related quality of life (HRQOL) has become one of the important endpoints in cancer treat- ments. However, a relatively small proportion of oncologists truly understand the concepts and uses of QOL assessments. In this article, I discuss psychometric properties that should be verified with QOL instruments, scope of the QOL concepts that should be assessed in oncology, how to choose the appropri- ate measures, and cross-cultural validation and statistical issues. Several examples of QOL assessments in recent clinical trials in oncology are also reviewed.

Breast Cancer 9:100-106, 2002.

Key words: Health-related quality of life, Health outcome, Breast cancer, Chemotherapy, Clinical trial

As in the developed Western countries, Japan has experienced the stagnation of economic growth and cultural maturity, and the demands placed on medicine from both patients and society have undergone rapid changes over the past 10 years. It is no longer sufficient to merely "prolong survival"; medical treatment must also help the patient main- tain a high "quality of life" (QOL). In recent years, moreover, expectations in these two areas have come to be seen as interlinked, with demand for individualized treatment that balances cost from the viewpoint of both the individual and society.

Confining ourselves to the field of cancer thera- py, we note that QOL has come to be an important indicator in the assessment of treatment outcome. A major reason behind this change in thinking, in addition to the general reasons mentioned above, is the reflection among many in the field that despite the great advances in basic biological studies in recent years, radical treatment of cancer is still imperfect, and contemporary treatment with sur- gery, radiation, and anticancer agents often causes serious harm to the patient that outweighs the ben- efits it brings.

Even if the importance of assessing QOL is

* ~lnstitute for Scientific Research of Stress, Pubhc Health Research Foun- dation (PHRF), and *%chad of Health Science and Nursing, Gradu- ate Schod of Medicine, Universi~ of Tokyo, Japan. Reprint requests to Kojiro Shimazuma, Institute for Saentific Research of Stress, PHRF, Nishiyama Kogyo Ochanomizu Building 5F, 1-2 13, Yushima, Bunkyo-ku, Tokyo 113-0034, Japan E-mail shmozuma@jmari.med.or.jp

Received January 10, 2002; accepted February 22, 2002

understood in principle, however, it is very difficult to express the subjective and qualitative concept of QOL in an objective, quantitative way that will be universally accepted. An examination of side effects, which is really only a subjective assessment on the part of the medical staff, may be mistaken for an objective indicator of QOL so that an assess- ment of the mental and social aspects of QOL may be thought essentially unnecessary in evaluating anticancer agents. Without considering the minori- ty of medical professionals who simply lack under- standing of the viewpoints of patients and society, in the following paper I will attempt to sum up the reasons why even the majority of conscientious physicians, who understand the importance of QOL assessments, may hesitate to adopt QOL assessment as an outcome indicator used in the selection of anticancer drugs. The main problems to be resolved are, among others, (1) establishing the theoretical basis for measuring something as qualitative as QOL (psychometry and the theory behind the measurement of QOL), (2) the scope of the conceptual framework for QOL to be evaluated in cancer treatment, (3) selecting and combining appropriate measures for different goals, (4) the problem of cross-cultural validation of a QOL mea- sure in multinational collaborative clinical trials, and (5) the appropriate handling of missing data in analysis.

The present report will outline the significance and problems of QOL assessments in oncology, and present some actual examples of such assess- ments with regard to breast cancer.

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Psychometric Properties Required in QOL Measures

When assessing QOL using a questionnaire sur- vey, it is of fundamental importance to adopt a questionnaire for which the reliability and validity have been confirmed, particularly in terms of psy- chometry. If QOL is measured using a question- naire for which these have not been substantiated, the correctness of the subsequent analysis may be questioned.

The distribution of characteristics in the popula- tion of a study (type of cancer, patient age, disease stage, treatment method, etc.) is also unlikely to be the same for subjects at the time a questionnaire is

Table 1. Psychometric Properties that Should Be Veri- fied with QOL Instruments

1. Reliability (1) Repeatability (test-retest) (2) Internal consistency (Cronbach's coefficient alpha)

2. Validity (1) Content validity (2) Criterion validity

a. Concurrent validity b. Predictive validity

(3) Construct validity a. Convergent validity b. Discriminant validity

(4) Responsiveness (Clinical usefulness)

developed. Therefore, as a rule it is desirable that a simple reliability coefficient and the validity of the scale are confirmed for the actual subject popula- tion in a study.

Table 1 shows the psychometric properties that should normally be included in a QOL instrument used in clinical cancer or other trials. The details are explained elsewhere 1).

Scope of the QOL Concepts that Should Be Assessed in Cancer Treatment

Discussion of the conceptual fi'amework of QOL has advanced based on the original 1947 WHO defi- nition of "health ''2) as "not merely the absence of disease, but complete physical, psychological and social well-being". This definition declares that health is not simply the amelioration of negative conditions giving rise to disease; it is also alms for a more positive state. Later, in 1998, it was proposed that "spiritual well-being" be added as an essential element in the definition of health 3). Fig 1 illustrates the fundamental concepts/domains of QOL arising from this definition of health that should be assessed in cancer patients. Most of the various domains shown with the ellipses are interrelated and cannot be clearly separated. Among them, the physical, functional (role), psychological (mental), and social aspects are referred to as health-related QOL (HRQOL), and most of the profile (question- naire)-type QOL instruments used in clinical can-

Fig 1. Conceptual framework of quality of life in oncology.

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cer studies today measure mainly these items. The spiritual aspect is thought to be particularly impor- tant in terminal stage cancer patients. However, assuming that cultural differences are large, not only are measurements of spiritual health difficult, but doubts have also been expressed as to whether medical intervention can bring improvements in this area (i.e., the problem of responsiveness). Whether or not the spiritual aspect of health should be dealt with in assessments of QOL is one of the major issues now confronting those in the field. Proposals have also been made for the addition of more detailed questions, since instructive informa- tion from the clinical setting is needed in the assessment of QOL associated with anticancer drugs 4). Thus, assessment of treatment-related symptoms, level of satisfaction with treatment, body image and sexual function are all important.

In any case, QOL is not a single variable but a construct including many domains and characteris- tics. In the assessment of QOL with various kinds of treatments, assessment should be made for each treatment and specified research goal, based on a variety of structural elements and from various angles.

Select ing a n d Combining Appropr ia t e Mea- sures

Instruments to measure HRQOL are commonly classified as (1) generic instruments and (2) dis- ease/condition-specific instruments (Table 2). The former are generally applied to assess the QOL of people who suffer no daily illness or patients with benign disease. They are also used occasionally to assess cancer survivors who have gone for a long period without a cancer recurrence. Generic instru- ments are further classified as those that allow cal- culation of "utility", and the health profile type. The generic instruments of health profile type that are often used in oncology are shown in Table 2. The advantage of using these generic instruments is that they allow comparison of QOL beyond the con- fines of the disease or condition, while the disad- vantage is that information specific to the disease or treatment is generally lacking. Therefore, when using a generic instrument to assess QOL with anticancer drugs, it is recommended that an addi- tional investigation of characteristic symptoms for that type of cancer or the symptoms associated with treatment be performed.

Cancer-specific instruments (Table 2) as dis- ease/condition-specific instruments are no differ-

Table 2. Health-Related Quality of Life Instruments Frequently Used in Cancer Clinical Trials

1. Generic instruments (Health profile type) (1) Medical Outcome Study Short From-36 (MOS SF-36) (2) Nottingham Health Profile (NHP) (3) Sickness Impact Profile (SIP) (4) Rotterdam Symptom Checklist (RSCL) (5) WHO QOL-26

2. Disease/condition-specific instruments (for cancer patients) (1) European Organization for Research and Treatment of

Cancer Quality of Life Questionnaire (EORTC QLQ) (2) Functional Assessment of Cancer Therapy (FACT) scale (3) Quality of Life Questionnaire for Cancer Patients

Treated with Anficancer Drugs (QOL-ACD)

ent from generic instruments in including the main domains of HRQOL, but the contents are more closely suited to each disease. For example, an inst rument for cancer patients will commonly include items on loss of appetite, weight loss, nau- sea, and hair loss. In addition, subscales for addi- tional concerns, also called modules, which include questions specifically for the treatment or type of disease, have been developed as options to be used together with the general scale or core question- naire in disease/condition-specific instruments; for example, a module for breast cancer and so on. These instruments are also often used to assess a drug in phase II or phase Ill clinical trials for cancer. The advantage of disease/condition-specific instru- ments is that with them it is easy to obtain clinically useful information, while the disadvantage is that it is virtually impossible to compare QOL not specifi- cally related to the disease or condition, and bias in the domains of QOL measured cannot be denied.

Of the generic QOL instruments shown in the Table 2, the two for which there is an official Japan- ese version are the Medical Outcome Study Short Form-36 (MOS SF-36) 5) and WHO QOL-26 +. Offi- cial Japanese versions for all the disease/condition- specific instruments shown in Table 2 have been developed.

Cross-Cul tural Val idat ion The opportunities in recent years for joint clini-

cal cancer trials involving Japan and Western coun- tries have increased dramatically with the develop- ment of new anticancer and other drugs. For this reason, establishment of techniques to allow proper QOL assessments using the same QOL measure across cultures and national borders is desired.

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Table 3. Commonly Used Translation Procedures of Quality of Life Instruments 2~)

Source Document in English

Step 1: Forward translation English --, Target language 2 native speakers of target language: 1 living in US, 1 living in native country (preferred) use simple language capture meaning of the item, rather than perform a literal translation

Step 2: Reconciliation of forward translations 1 native speaker of target language (preferred) provide alternative translation (s), if necessary

Step 3: Back translation of reconciled version Target language -~ English 1 or 2 native English speaker no previous exposure to the instrument use simple language capture the meaning of the item

Step 4: Independent reviews by 3-4 bilingual experts 1 linguist, 1 with knowledge of medical/health/psychological concepts, and 1 language coordinator

Step 5: Spelling and grammatical language verification 1 bilingual expert, usually the language coordinator

Step 6: Pretesting with patients (n -- 10-20)

Table 4. Current Status in the Development of Japanese Versions of the Health-Related Quality of Life Instru- ments Developed in Western Countries (Dec. 2001)

Developed Japanese versions

1. EORTC QLQ (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) (1) Core questionnaire: C30 (2) Disease-specific modules: BR23 (breast cancer), LC13 (lung cancer)

2. FACT (Functional Assessment of Cancer Therapy) scale (1) General instrument: FACT-G (2) Subscales for additional concerns: FACT-B (breast cancer), L (lung cancer), B1 (bladder cancer), P (prostate cancer), Cx

(cervical cancer), O (ovarian cancer), An (anemia), F (fatigue), Taxane (taxane toxicity), GOG-Ntx (neurotoxicity), Sp (spirituality), ES (endocrine-related symptoms)

Under development

1. EORTC QLQ Disease-specific modules: STO22 (gastric cancer), OES24 (esophageal cancer)

2. FACF Subscales for additional concerns: FAACT (anorexia and cachexia), FACT-C (colon cancer), Pal (palliative care), BMT (bone marrow transplantation), H and N (head and neck cancer), BRM (immunotherapy), Ga (gastric cancer, development by collaboration with the US researchers), etc.

To compare differences between countries and cultures, the first key matter is translation of mate- rials to accurately convey meaning in the language of each country. This generally requires rigorous translation work as illustrated in Table 3.

Through this kind of work, QOL instruments developed in the West to assess cancer treatment

can now be used in Japan. Two major such instru- ments are the European Organization for Research and Treatment of Cancer Quality of Life Question- naire (EORTC QLQ) 7) and the Functional Assess- ment of Cancer Therapy (FACT) scale 8). Table 4 shows the current status of the development of Japanese versions of the core questionnaires and

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disease and treatment-specific modules for these scales. Reliability and validity have been verified for the Japanese versions of the EORTC QLQ-C309) for lung cancer patients, and EORTC QLQ-301~ FACT-G (general) 13) and FACT-B (breast cancer) 13) for breast cancer patients. The reliability and validi- ty of FACT-Sp (spiritual well-being) for patients with several types of cancer, FACT-G and FACT-L (lung cancer) for lung cancer patients, and EORTC QLQ-BR23 (breast cancer) and FACT-Taxane (tax- ane toxicity) for breast cancer patients are now in the process of being verified.

Points of Caution in QOL Surveys, and Appro- priate Handling of Missing Data in Analysis

There are several sources of bias that should be taken into consideration in assessing QOL in oncol- ogy. In addition to medical factors such as disease progression and existing treatments, these include, age, marital status, occupation, level of education, and family income 14). All are factors that may influ- ence the results of the analysis, and should be understood as fully as possible at the start of the survey. Treatment baseline is an essential survey point, followed by a minimum of one or two points during and after the treatment.

Missing data tend to increase in QOL studies, particularly those of advanced cancer patients. Before analyzing the collected scores, the cause of the missing data should be identified. Missing data can be broadly classified qualitatively as (1) miss- ing completely at random (MCAR), (2) missing at random (MAR), and (3) missing not at random (MNAR). In many cases the analysis technique dif- fers according to the reason for the missing dats s).

Actual QOL A s s e s s m e n t with Ant icancer Drugs in Japan

The National Surgical Adjuvant Study of Breast Cancer (N-SAS BC)-0116) is the first breast cancer clinical trial in Japan in which a QOL assessment was fully incorporated. This trial was begun in October 1996 and is a randomized comparison of 6 cycles of cyclo-phosphamide + methotrexate + 5- FU (CMF) and 2-year oral administration of UFT in pathological high-risk, postoperative breast cancer patients negative for lymph node metastasis. The primary endpoint was disease-free survival (DFS), and QOL was included among the secondary end- points along with survival time, adverse events, and cost. Because this was a trial to prove the equiva- lency of the primary endpoint of DFS, the evalua-

tion results for the secondary endpoints have a very deep significance. Just as with major cancer clinical trial groups in the West, such as the Nation- al Surgical Adjuvant Breast and Bowel Project (NSABP), South West Oncology Group (SWOG), and EORTC, the official QOL assessment commit- tee is recognized as a subcommittee in the clinical trial, and several clinicians, biostatisticians, data managers, and others were involved regularly from the stage of protocol development in resolving diffi- culties. In the initial stage, the EORTC QLQ-C30 and the Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL- ACD) 17,18) were used concurrently for about 300 sub- jects (Study I). Now, for the next 300 patients, QOL is being assessed over time, using the EORTC QLQ-C30, BR23, and FACT-B concurrently (Study 1I ). Interim reports have been published on the results of attempts to verify the reliability and validi- ty of the measures, as well as a comparison of QOL scores for Study 110-12)

The Japan Clinical Oncology Group (JCOG) 9803 is an example of QOL assessment in a large- scale study of metastatic breast cancer patients. JCOG9803 was a feasibility study for QOL assess- ment, conducted in parallel with JCOG9802. JCOG9802 was a randomized comparison of 3 groups treated with cyclophosphamide + doxoru- bicin (CA), docetaxel (DOC), and alternating thera- py with CA and DOC. An organization called the 'QOL Unit' was created in the data center for the JCOG, which dealt with problems in QOL assess- ment. The measures used in the JCOG9803 were FACT-B and the FACT subscale for taxane toxicity.

Next, while not a clinical trial, the ~I'ask-force for the Development of QOL Assessments and Analy- sis Guidelines for Breast Cancer' was begun in May 1999 by the Japanese Breast Cancer Society 0BCS). An attempt was made to develop a breast cancer module (QOL-ACD-B) for the QOL-ACD, and guide- lines for QOL assessments in breast cancer clinical studies were prepared based on critical review of QOL reports, including those in Western countries, over the past 10 years 19).

Actual QOL A s s e s s m e n t with Ant icancer Drugs in Other Countries

Here I shall briefly introduce notable QOL research reports for breast cancer recently pub- lished in academic journals.

First is the QOL assessment in a clinical trial of aromatase inhibitors (hormonal therapy for breast

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cancer) by the Swiss Group for Clinical Cancer Research (SAKK) TM. The aromatase inhibitor formestane, administered once every 2 weeks by intramuscular injection, was compared with mege- strol acetate (MGA) taken orally on consecutive days as a second-line therapy in 177 postmeno- pausal breast cancer patients who had developed resistance to tamoxifen 21~. QOL was measured as a secondary endpoint. The measure used was the visual analogue scale (VAS) associated with the multiple QOL domains used in the International Breast Cancer Study Group (IBCSG). The overall response rate was 83%. Analysis was done with the baseline QOL score controlled, and no significant difference was found between the QOL scores of the two groups at the time of relapse. However, baseline QOL was a strong predictive factor of QOL during therapy.

Next is a 13 country multinational collaborative comparison study called the ZEBRA-study of LHRH analogue against CMF, which investigated 689 stage lI breast cancer patients positive for lymph node metastasis 22). A preliminary study was conducted with the aim of identifying problem points in inter-cultural studies measuring QOL. The measure used was the Rotterdam Symptom Check- list (RSCL) 23) as a general instrument (usefulness had been confirmed even for clinical cancer trials). Measurements were conducted at baseline and 3 months. The response rate at baseline and 3 months was 78% and 68%, respectively. The discrepancy between countries in the reliability coefficient in the physical and psychological subscales was a good 0.68-0.90, although a fairly large discrepancy of 0.42-0.89 was seen in the subscale for activity. Sig- nificant differences were seen in the QOL score bet- ween cultures in all the subscales at baseline, and in all except the physical subscale at 3 months. This report highlighted the difficulties faced in assess- ing QOL in multinational collaborative clinical trials.

Next is a report on the influence of trastuzumab (Herceptin ~) therapy on QOL 24). Although trastuzum- ab therapy for metastatic breast cancer with overex- pression of HER2 is a current focus of attention, this was the first report on the QOL of patients undergoing treatment with this drug. The instru- ment used was the EORTC QLQ-C30. First, in a phase II study of 222 subjects, there was no deteri- oration in QOL following treatment with trastuzum- ab administered alone (baseline response rate 93%). Then, with the aim of comparing a chemother- apy-only group and a combination group using this

drug, a phase m study with 431 subjects was con- ducted (baseline response rate 92%) which found no difference between the groups in QOL during the therapy. However, upon closer examination, in the chemotherapy-only group there was a slight decline throughout the treatment period in the physical functioning, role functioning, and fatigue domains of QOL, whereas in the combination group there was a slight decline in QOL at certain times only related to the social functioning, role functioning and fatigue domains. In summary, in the doses and schedules used in these studies, trastu- zumab is not associated with worsening of HRQOL.

In other places, QOL assessments have been conducted even in breast cancer preventive trials. Because a significant difference was seen between tamoxifen and control groups with the primary endpoint of breast cancer incidence (tamoxifen had a preventive effect), the NSABP P-1 study (Breast Cancer Prevention Trial: BCPT), famous for being discontinued before completion, provided the results of QOL measurements as a secondary end- point 2~). The subjects were 11,064 women enrolled in that study. QOL data fl'om baseline and the fol- lowing 36 months were analyzed. The measure used was the Center for Epidemiological Studies- Depression Scale (CES-D) as the psychological scale and MOS SF-36 as the QOL scale. A sexual functioning scale and symptom check list were also used. There was no significant difference in the CES-D score between the tamoxifen and control groups, nor was there a significant difference in the physical and psychological scores of the SF-36. The mean number of symptom complaints, mainly relat- ed to vasomotor and gynecological symptoms, was significantly greater in the tamoxifen group. Sexual activity was overall the same, but reports of regular or serious sexual dysfunction were significantly greater in the tamoxifen group. We may conclude from this that patients should be informed of the increase in vasomotor and gynecological symp- toms, and the greater likelihood of sexual function problems, in women taking tamoxifen. However, the weight gain and depressive symptoms predict- ed for the tamoxifen group before the start of the trial were not seen in these healthy subjects. This is good news for women who will undergo preventive administration of tamoxifen in the future.

Conc lus ion

This article has outlined the importance of QOL

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assessment as an outcome indicator in evaluating cancer treatments, and reviewed the applications of such assessments. In the 21st century, we may look forward to a great deal of evidence that will be truly beneficial in the selection of anticancer treatments, based on the results of high quality QOL assess- ments.

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